Adequate muscle mass is important for normal physical function and whole-body intermediary metabolism (including fuel metabolism). Men have more muscle mass than women, and obese people have a greater than expected muscle mass for their height (compared to lean individuals). However, this increase in muscle mass is less in women than in men. In contrast, loss of muscle mass during fasting or chronic underfeeding is greater in men and lean persons than in women and obese persons. The mechanisms responsible for these differences in muscle mass regulation during anabolic and catabolic conditions are not known. The main purpose of the proposed studies is to determine the effects of sex and adiposity on changes in skeletal muscle protein synthesis (MPS) in response to the major physiological conditions that stimulate (i.e., increased amino acid availability and resistance exercise) or inhibit (i.e., fasting) MPS. We anticipate that differences in muscle protein metabolism between men and women, and lean and obese individuals, that may be subtle or undetectable during basal conditions at rest, may become more apparent during those physiological conditions. We hypothesize that the amino acid- and exercise-induced stimulation of MPS is greater in men than women and that increased adiposity augments these responses both in men and women. However, during catabolic conditions the attenuation of MPS is greater in men than women and increased adiposity diminishes the fasting-induced reduction of MPS. Furthermore, we hypothesize that the differences between men and women are, in part, due to the presence of female sex-hormones. These hypotheses will be tested by evaluating MPS and the activity of intracellular factors that regulate protein synthesis in human subjects during 1) basal resting conditions, 2) during amino acid infusion, 3) after resistance leg exercise, and 4) after prolonged fasting, by using stable isotope labeled amino acid tracer infusion and assessment of the phosphorylation of key intracellular factors involved in the regulation of protein synthesis. The knowledge obtained from these studies will increase our understanding of the interactions between a person's sex and adiposity and the intracellular factors involved in protein synthesis and the regulation of MPS (and therefore muscle mass). This information should prove useful in developing novel therapeutic approaches aimed at maintaining muscle mass throughout a person's lifespan and in patients with conditions associated with muscle wasting.